While much has been elucidated recently regarding immunologic and virologic factors involved informal and long term non-progressive infection, it is not yet known why some patients progress more rapidly. In order to gain an understanding of the correlates of rapid HIV-1 disease progression, longitudinal studies of lymphocyte proliferation, bulk and memory CTL responses, and viral sequences variation were performed on a patient who presented with acute HIV-1 seroconversion syndrome in 1992 and died 45 month later. The subject displayed a rapid clinical course with sustained high viral loads despite use of multiple antiretroviral agents in combination; however, high virus isolates were consistently non-syncytia forming. No HIV-specific lymphocyte proliferative responses were seen even early in disease course. In vivo activated CTL directed against Env and Pol epitopes were detected initially but were lost quickly. CTLp activity was detected against Env and Pol epitopes up until the time of the patient's death, but in decreasing amounts, Epitope mapping suggested that these CTL were narrowly directed and that new epitopes were not targeted as disease progressed. Autologous viral sequencing showed rapid emergence of variants within regions recognized by CTL. Peptides based upon viral variants were less well recognized by CTL in standard chromium release assays. Longitudinal study of HIV-specific immune responses in a patient with rapidly progressive disease demonstrated lack of HIV-specific lymphocyte proliferation, rapid loss of in vivo activated CTL, and a narrowly directly HIV-specific memory CTL response which did not broaden despite the emergence of viral variants. Viral sequencing suggest a potential role of immune pressure. Further characterization of the immune response in rapid progressors may elucidate factors responsible for HIV progression and provide clues to control of the virus in this unfortunate subset of patients.